The interplay between innate and adaptive immunity in cancer shapes the productivity of cancer immunosurveillance

Abstract

The immune system is a vital determinant of cancer and shapes its trajectory. Notably, the immune reaction to cancer harbors dual potential for suppressing or promoting cancer development and progression. This polarity of the immune response is determined, in part, by the character of the interplay between innate and adaptive immunity. On the one hand, the innate immune compartment is a necessary proponent of cancer immunity by supporting an immunostimulatory state that enables T cell immunosurveillance. However, in the setting of cancer, innate immune cells are commonly polarized with immune-suppressive properties and as a result, orchestrate a tolerogenic niche that interferes with the cytotoxic potential of tumor antigen-specific T cells. Here, we discuss the role of innate immunity as a positive and negative regulator of adaptive immunosurveillance; moreover, we highlight how tumor cells may skew leukocytes toward an immunosuppressive state and, as such, subvert the phenotypic plasticity of the immune compartment to advance disease progression. These observations establish the precedent for novel therapeutic strategies that aim to restore the tumor microenvironment to an immunoreactive state and, in doing so, condition and maintain the immunogenicity of tumors to yield deep and durable responses to immunotherapy.

Keywords: T cells; cancer; conditioning therapy; immune evasion; immunotherapy; maintenance therapy; myeloid cells.

Figure 1.. The orientation and quality of the immune reaction defines the sensitivity of tumors to immunotherapy.

The immune reaction to cancer is determined by the orientation of the immune response, which refers to its inclination to support (i.e. immune stimulatory) or inhibit (i.e. immune suppressive) T cell activation, and the quality of the immune response, which refers to its ability to mediate T cell-dependent anti-tumor immunity. The quality of the immune response is dependent on multiple factors (e.g. dendritic cell infiltration and T cell chemoattractants) which determine the degree of T cell infiltration. T cell infiltration can range from “cold” (i.e. poor infiltration) to “hot” (i.e. brisk infiltration). Together, the orientation and quality of the immune response influence the likelihood of response to immunotherapy.

Figure 2.. Adaptive immunity in cancer is defined by priming and effector phases.

T cell immunosurveillance in cancer is dependent on steps (1–4) that support T cell priming and activation (Priming Phase) and steps (5–6) which involve T cell effector activity (Effector Phase). Steps associated with the Priming Phase include (1) the release of tumor antigens which are captured by antigen presenting cells (APCs), (2) cross-presentation of tumor antigens to T cells by APCs in tumor-draining lymph nodes, (3) priming and activation of naïve T cells by antigen-loaded APCs, and (4) trafficking of T cells from lymph node into the blood stream and to tumors. Steps associated with the Effector Phase include (5) T cell infiltration into tumors and (6) T cell recognition and elimination of tumor cells.

Figure 3.. A biphasic approach to cancer immunotherapy.

(a) Conceptual model displaying two phases of immunotherapy. In the first phase, tumors are “conditioned” with sensitivity to immunotherapy. In the setting of immunotherapy, tumor cells may then adapt to immune pressure (i.e. acquired resistance) which undermines the success of immunotherapy. As such, the second phase incorporates strategies to “maintain” tumors as immune sensitive and to prevent their reversion to immune resistant. (b) Correlation plot showing the relationship between the likelihood of responding to immunotherapy and the quality of the immune reaction to cancer. The “conditioning” phase of therapy aims to shift an immune resistant tumor (blue circle) to immune sensitive (orange circle). However, tumors may also acquire therapeutic resistance (e.g. recruitment of immune suppressive cells) which abate a productive immune response. The “maintenance” phase of therapy aims to prevent this shift to a state (grey circle) of decreased likelihood of response to immunotherapy.